Background

The use of antidepressants as aids to smoking cessation seems reasonable.
Nicotine may act as an antidepressant, and some smokers become depressed
after quitting. Trials of antidepressants have had promising but also mixed
results. This study was designed to evaluate a sustained release formulation
of buproprion as an aid to smoking cessation (this drug was recently approved
by the FDA for this purpose).

Methods

Subjects

Subjects were recruited (at three sites in the United States) through
advertisements and were eligible if they were over 18 years of age, had
smoked 15 cigarettes or more daily for at least one year and were generally
in good health.

Exclusions: Predisposition to seizures; pregnancy or lactation;
unstable medical or psychiatric conditions; current depression; anorexia
or bulimia; alcohol or other non-nicotine dependence; current use of psychotropic
medications, non-cigarette tobacco products or nicotine replacement therapy.

Reported abstinence from smoking was validated by measuring the content
of carbon monoxide in expired air.

Analysis

Smoking abstinence was assessed by two measures:

The point prevalence abstinence rate was defined as the rate of abstinence
during the preceding week. Thus, if 30% of patients at week 6 were abstinent
during the previous week (by history and confirmed by CO measurement),
then the point prevalence abstinence rate at week 6 would have been 30%.

The rate of continuous abstinence required abstinence at all previous measurement
points. Thus, if 20% of patients at week 6 had been continuously abstinent
since quitting smoking at week 1, the rate of continuous abstinence at
week 6 would have been 20%.

Smoking abstinence was compared between groups on an intention to treat
basis. Subjects who missed a follow-up visit were assumed to have smoked
during the preceding interval.

Withdrawal symptoms were recorded in a diary and a daily symptom
score was calculated during the study drug period, using a 9-item instrument.

The Beck Depression Inventory was administered at baseline and
at weeks 2 and 6 after the target quitting date.

Weight change was analyzed in subjects who were continuously
abstinent during the treatment phase.

Results

Subjects and completion rates

612 subjects were enrolled, 153 in each of the four treatment groups.

Baseline characteristics were not significantly different between the
treatment groups. These included (averaged across the four groups):

Age: 44 years; Female: 55%; White race: 96%

Cigarettes smoked / day: 27

Number of previous attempts at quitting: 4

219 subjects (36%) failed to complete all twelve months of the study; 148
dropped out during the 7 week treatment phase. The majority (89%) of dropouts
withdrew consent for various reasons, including perceived lack of benefit;
there were 15 dropouts due to adverse reactions and one death. Increasing
doses of bupropion were associated with decreasing dropout rates (43% in
the placebo group; 29% in the 300 mg group).

Smoking cessation rates

Time

Parameter

Placebo

100 mg

150 mg

300 mg

1 week after quitting

Not smoking

19%

31%

32%

49%

6 weeks after quitting
(end of treatment)

Not smoking (point prevalence)

19.0%

28.8%

38.6%

44.2%

Continuous abstinence

10.5%

13.7%

18.3%

24.4%

12 months(end of study)

Not smoking (point prevalence)

12.4%

19.6%

22.9%

23.1%

Weight change

Among the 103 subjects who were continuously abstinent during the treatment
period, weight gain was 2.9 kg in the placebo group, 2.3 kg in the 100
and 150 mg buproprion groups and 1.5 kg in the 300 mg group (p=0.003).
At six months, however, there was no significant difference among the groups
for the 59 subjects who remained continuously abstinent.

Symptoms

There was no significant effect of treatment on the Beck Depression
Inventory scales.

Surprisingly, the only effect of treatment on the nicotine withdrawal
score was a significant increase in the 100 mg group, compared with
the placebo and the 150 mg and 300 mg groups.

Adverse effects

Adverse effects were similar in all four groups, although dry mouth
occurred more frequently with the higher doses of buproprion (13%). Withdrawals
due to adverse effects occurred in 8, 9, 7 and 13 patients in the four
groups respectively. There was one death in a 63 year old woman with preexisting
cardiomyopathy (cardio-pulmonary arrest 4 days after completing the 300
mg buproprion treatment).

Author's discussion

The authors note that buproprion was effective in increasing the rate of
smoking abstinence. Although there was no significant difference between
the 150 mg and the 300 mg doses in terms of point-prevalence abstinence,
the rate of continuous abstinence at 6 weeks was significantly increased
only in the 300 mg group, and this is the dose that the authors feel is
most appropriate.

The length of treatment (7 weeks) was chosen based on prior studies
with nicotine replacement. Longer treatment with buproprion may be appropriate,
however, particularly since the effect on limiting weight gain only persisted
during active treatment.

The authors speculate that the efficacy of buproprion may be due to
its effect on adrenergic and dopaminergic mechanisms in the brain, rather
than on its anti-depressant properties. Although no increase in rates of
seizures was noted in this study, the sample size was too small to reliably
assess this potential issue (bupropion used as an antidepressant is associated
with a small increase in seizure risk). [see note
below]

Comment

In this study, the antidepressant buproprion prescribed for 7 weeks was
found to be effective in increasing the rates of abstinence from smoking,
and was well tolerated. Although there was little difference between the
doses of 150 mg and 300 mg daily, the authors recommend the higher dose
based on its greater effect on continuous abstinence from smoking at the
end of the treatment period.

Unfortunately, there was a fairly high dropout rate (between 29% and
43%). Importantly, the dropout rate decreased with increasing doses of
the drug, and dropouts were automatically assumed to have resumed smoking
(according to the methods section of the article). This fact could have
biased the results in favor of buproprion. This issue might have been clarified
had the authors reported the results in the subgroup that did not drop
out, in addition to the "intention to treat" analysis of all subjects presented
here.

This caveat aside, there is a great need for drugs that will help patients
stop smoking, and buproprion may well turn out to be such an agent. Issues
that will need to be clarified include the optimal duration of therapy,
the effect of buproprion compared with and in conjunction with nicotine
replacement therapy, and the role of other anti-depressant medications.

November 7, 1997

Important Note

In the original version of this summary, I stated that "antidepressents
are associated with a small increase in seizure risk". This is inaccurate.
In fact, "bupropion used as an antidepressant is associated with
a small increase in seizure risk". This has now been rectified.

According to the PDR, the risk of seizure associated with sustained
release bupropion at a daily dose of 300 mg is 0.1% (1/1000). This is small,
but not negligeable. Multiple precautions are recommended to reduce the
seizure risk (the drug should be avoided in patients with a history of
seizure, with conditions that predispose to seizures or who are taking
other medications that lower seizure threshhold).

January 7, 1998

References

Reader Comments

January 7, 1998

In a letter to me, Dr. Richard Hurt (corresponding author of the study)
points out that there was a dose-response effect throughout the treatment
phase and up to one year. This was one of the major reasons the authors
recommended the 300 mg dose as the best dose to be used.

Date: Sun, 15 Mar 1998
From: melissa prew <mprew@oaktree.net>

I have a question regarding the way the results were reported in this
article. I don't feel point prevalence data at 12 months necessarily reflects
the effects of a medication administered 10 months ago. Isn't it possible
patients resumed smoking at some point during the study, and then managed
to quit again "cold turkey" independant of bupropion therapy? I don't understand
why continuous quit data was reported only at 6 weeks and not reported
at 12 months.

In clinical practice I don't really care if my patients are able to
remain abstinent from smoking for 1 week. I want to know if therapy with
bupropion is more effective on a continuous rate for 1 year when compared
to placebo. Why were the continuous quit rates at 12 months not included??

The problem with continuous quit rates at 12 months is that any
patient who smoked even once during the initial 6 weeks was classified
as being not continuously abstinent. That is why the continuous quit rates
at 6 weeks were so low (24.4% at the highest bupropion dose vs. 10.5% placebo).
I'm not sure that a single, short-term relapse is significant. What I would
have liked to see would be some measure like abstinence over the previous
two months, at one year. I agree with you that point-prevalence at one
year, based only on smoking during the previous 7 days, may not be the
ideal measure of success. -- mj

November 19, 1998

Letters
to the editor about this article were published in the February 26,
1998 NEJM. These are about the appropriate dose of buproprion and about
whether the subjects were truly blinded.